Novel 2, 2, 6, 6-tetrachloro-1-hydroxycyclohexanecarbamide



United States Patent (3 This is a division of application Ser. No.251,731, filed Jan. 16, 1963, now US. Patent 3,236,874.2,6-dichlorobenzonitrile has recently been found to have outstandingherbicidal properties with particular toxicity to germinating seeds.This invention relates to a novel process for preparing this compoundand a novel intermediate from readily available starting materials.

According to the present invention, a process for preparing2,6-dichlorobenzonitrile comprises subjecting a cyclohexane derivativeto an elevated temperature suflicient to effect conversion to saidnitrile, said cyclohexane derivative having the general formula:

X Y or o1 wherein n=0 and X represents a halogen atom, particularly achlorine atom; or the group OR, wherein R represents the radical of amonobasic organic acid, or of a poly basic organic or inorganic acidwhose remaining acidic function or functions is or are present as suchor in salt or ester form and Y represents the CN group;

X represents a hydroxyl group and Y represents the group CONI-I Zrepresents a chlorine atom;

n=1 and Y represents the group CONH X and Z together forming a secondbond between their respective ring carbon atoms (indicated by a dottedline), and Z represents a chlorine atom.

X may represent the group OR wherein R represents the radical of amonobasic organic acid or of a polybasic organic or inorganic acid, theremaining acidic functions thereof being present as such or in salt orester form. The organic acid may be saturated or unsaturated and may bealiphatic, alicyclic, aromatic or of mixed type, for example, analiphatic substituted aromatic acid or an aromatic substituted aliphaticacid. The acid may be unsubstituted or substituted, for example, byhalogen, preferably chlorine. The acid may be a carboxylic acid or asulphonic acid. Since the group OR is eliminated in the thermalconversion process, R advantageously represents a relatively small groupof not more than 7 carbon atoms. Preferably R represents the radical ofan aliphatic carboxylic acid or sulphonic acid of 1 to 4 carbon atoms orof a chlorinated derivative thereof, for example, acetic acid or ahomologous acid, monochloroacetic acid, trichloroacetic acid or methanesulphonic acid, particularly acetic acid, or the radical of an aromaticacid such as benzoic acid or p-toluenesulphonic acid. Examples ofsuitable polybasic acids are oxalic acid, succinic acid, phthalic acidor one of its isomers, sulphuric acid or phosphoric acid. Remaining acidfunctions present in salt form are preferably alkali or alkaline earthmetal salts. Remaining acidic functions present in ester form may beesters of aliphatic alcohols, preferably of aliphatic alcoholscontaining 1 to 4 carbon atoms in the molecule, particularly of methanolor ethanol, but are preferably esters of the cyanohydrin of2,2,6,6-tetrachlorocyclohexanone. These preferred compounds are thusnormal esters of polybasic organic or inorganic acids with saidcyanohydrin, for example the diester of sulphuric acid of formula:

CN O.SO2.0 CN 01 c1 c1 01 01 01 c1 01 or of oxalic acid of formula CN0.0 0.00.0 CN

or O1 c1 01 The temperature at which the conversion of the aforesaidcyclohexane derivative to the nitrile is elfected will depend to someextent on the nature of the atom or group which X represents and shouldpreferably be sufiicient only to induce the desired chemicalrearrangement. In general, a temperature of at least 200 C. is required.A temperature in the range 200 to 300 C. is particularly suitable, atemperature in the range 210 to 270 C. being preferred.

When Y represents the group CONH it is advantageous to carry out thepyrolysis in presence of a dehydrating agent, i.e. a compound orcatalyst which facilitates the removal of the elements of water from theamide group, for example, phosphorus pentoxide, oxychloride,trichloride, pentachloride or mixtures of phosphorus oxychloride andphosphorus trichloride or pentachloride. Phosphorus pentoxide is thepreferred dehydrating agent.

The conversion may be effected by heating the cyclohexane derivative inabsence of a liquid reaction medium, or .a liquid reaction medium whichmay be solvent for the cyclohexane derivative and/or for the2,6-dichlorobenzonitrile, and which is of suitable high boiling pointand is stable 'at the conversion temperature employed, may be used. Aneffective waylof carrying out the conversion in some cases comprisescontacting the cyclohexane derivative with molten, paraflin waxmaintained at or slightly above the appropriate conversion temperature.The 2,6-dichlorobenzonitrile formed distills or sublimes from the moltenmass and is collected in' a cooled receiver; this process may be carriedout under reduced pressure. The conversion may be effected in fluid orsolid phase. It is preferably carried out under atmospheric pressure butlower or higher pressures may be used if desired. The process may becarried out batchwise, for example, by heating in a glass or othercorrosion resistant vessel fitted with reflux condenser and a vent forthe evolved gases. Advantageously, a continuous procedure is employed inwhich the starting material is passed through a heated tube, forexample, of glass, quartz, porcelain or corrosion resistant metal. Thetube may be empty or it may be packed with either an inert packingmaterial or with a catalytically active material. The conversion mayalso be effected by contacting the vaporized starting material with aglowing filament, for example, of platinum.

The above cyclohexane derivatives used as starting materials in theprocess of the invention are novel compounds. According to an extensionof this process, compounds of the above general formula, wherein 11:0, Zrepresents a chlorine atom and X represents a chlorine or bromine atomare prepared by treating the corrwponding cyanohydrin with a suitablechlorinating or brominating agent for example, thionyl chloride orthionyl bromide. A particularly suitable method comprises treating thecyanohydrin with thionyl chloride or thionyl bromide, preferably with anexcess thereof, in presence of a tertiary nitrogenous base, for example,pyridine, and preferably in presence of a minor proportion thereof. Thisprocess may be effected in absence of a solvent or an inert solvent, forexample, a chlorinated hydrocarbon, such as carbon tetrachloride, may beemployed. Suitably, the reactants or reactants and inert solvent, areheated together under reflux for a short period of hours, after whichthe volatile material is removed. On treating the residue With methanol,l,2,2,6,6-pentachlorocyclohexanecarbonitrile or its l-bromo analogue isobtained in crystalline form. If desired, it can be purified byrecrystallization from a solvent. A mixture of chloroform and ether hasbeen found to be a suitable solvent for this purpose.

Cyclohexane derivatives of the above general formula in which Xrepresents the group OR and R represents the radical of an organic orinorganic acid as hereinbefore specified, may be prepared by treatingthe corresponding cyanohydrin with an esterifying agent according tomethods Well known in the art. Preferably the cyanohydrin is treatedwith the anhydride of the acid ROH, or with the acid halide, suitablythe acid chloride, optionally in presence of a minor proportion of atertiary nitrogenous base, for example, pyridine. The ester ofcyanohydrin isolated from the reaction mixture is, in general, a solidand can, if desired, be purified by recrystallization from a solvent.Chlorinated hydrocarbon solvents, for example, chloroform, are suitablefor this purpose. The cyanohydrin may also be treated with the acid ROH,advantageously with simultaneous removal of the water formed in thereaction and, where organic acids are used, preferably in presence of anesterification catalyst, for example, hydrogen chloride or concentratedsulphuric acid. Alternatively the cyanohydrin may be esterified by aninterchange reaction with an ester of the acid ROH with a readilyvolatile alcohol, for example, methyl alcohol or ethyl alcohol.

Where the acid ROH contains one or more additional acidic groups, thesefurther acidic groups may be present as such or in the form of salts oresters. Advantageously, each acid group of the acid ROH is esterified bya molecule of the above cyanohydrin.

According to another extension of the process of the invention, theamide of the formula HO CONH:

used as starting material for conversion to 2,6-dichlorobenzonitrile isprepared by hydrolysis of the corresponding cyanohydrin or of1,2,2,6,-pentachlorocyclohexanecarbonitrile. This is suitably effectedby treating the nitrile with concentrated sulphuric acid. This reactionis preferably carried out at a temperature in the range 50 to 95 C. whena reaction time of about 30 minutes in general suffices. The reactionmixture is then poured on to ice or into water or ice and Water and thesolid product collected and, if desired, recrystallized. An aromatichydrocarbon solvent such as benzene or a mixture of ether and lightpetroleum are suitable solvents for this purpose.

According to another extension of the process of the invention, thecompound of formula ooNrn used as starting material for conversion to2,6-dichlorobenzonitrile, is prepared by treating the epoxy amide offormula CONHa C1 Cl with an aqueous solution of a strong acid at anelevated temperature. Suitable for this purpose is a 50% by weightaqueous solution of sulphuric acid at a temperature in the range 70 C.up to the boiling point. When the epoxyamide has dissolved, the solutionis diluted with water, preferably after cooling, and the resulting solidproduct, collected and if desired, recrystallized from a solvent.Methanol or aqueous ethanol is a suitable solvent. The precise structureof the product has not been established with certainty but it isbelieved to be the 3-hydroxy compound CONH:

The above epoxy-amide may, according to a further extension of theprocess of the invention, be prepared by alkaline hydrolysis of thecorresponding epoxy-nitrile.

The hydrolysis is suitably etfected by treating the epoxynitrile with anaqueous or aqueous alcoholic solution of an alkali metal hydroxide,particularly potassium hydroxide. The hydrolysis is carried out at atemperature low enough to avoid opening the epoxide ring. In general,temperatures below 30 C. and preferably below 20 C. are suitable.Prolonged reaction times, for example, 12 to 24 hours are in generalnecessary.

Alternatively, and according to another extension of the process of theinvention, the above epoxy-amide is prepared by treating2,2,6,6-tetrachloro-l-hydroxycyclohexanecarbonamide with a base or basicacting substance. The base or basic acting substance used may be analkali metal hydroxide, carbonate or bicarbonate or it may be an organicnitrogenous base, for example, an aliphatic secondary or tertiary amine,particularly diethylamine or triethylamine or a heterocyclic nitrogenousbase, for example, pyridine. The treatment is advantageously effected inpresence of a solvent, for example, water, an alcohol or an aqueousalcohol.

According to a further extension of the process of the invention, thecyanohydrin of formula HO GN which is a novel compound, is prepared bytreating 2,2, 6,o-tetrachlorocyclohexanone with hydrogen cyanide. The

reaction may be effected by simply mixing the ketone, or a solutionthereof in a suitable solvent, with anhydrous hydrogen cyanide,preferably with a small excess thereof, for example to excess. Analiphatic alcohol of 1 to 4 carbon atoms may be used as the solvent.Preferably a trace of potassium or sodium cyanide or other basiccatalyst is added to the reaction mixture. When the reaction iscomplete, the catalyst is neutralized with the requisite amount ofsulfuric acid and the excess hydrogen cyanide is distilled from themixture.

Instead of using anhydrous hydrogen cyanide per se, the hydrogen cyanidemay be generated in situ from an alkali metal cyanide by treatment withan acid, for example, glacial acetic acid, sulfuric acid or hydrogenchloride, or with an aqueous solution of a mineral acid, for exampic 30%aqueous sulfuric acid. The cyanohydrin may also be prepared from2,2,6,6-tetrachlorocyclohexanone by an exchange reaction with thecyanohydrin of an aldehyde or of another ketone, said aldehyde or ketonebeing preferably readily volatile compounds. The cyanohydrin of acetoneis particularly suitable for this purpose.

By treating 2,2,6,6-tetrachlorocyclohexanone with hydrogen cyanide inpresence of an alkali metal cyanide, especially with an excess of alkalimetal cyanide, or the cyanohydrin of 2,2,6,6-tetrachlorocyclohexanonewith an alkali metal cyanide, an epoxy-nitrile is formed which has thefollowing formula:

the reaction may be effected in presence of a solvent, an aliphaticalcohol of 1 to 4 carbon atoms, particularly ethanol, being suitable forthis purpose. This epoxy-nitrile is a novel compound and is a usefulintermediate. This compound and its preparation are further features ofthe invention.

According to the still further extension of the process of theinvention, the 2,2,6,G-tetrachlorocyclohexanone is prepared by treatingcyclohexanol with chlorine. The reaction may be effected in presence ofactinic light and optionally also in presence of an organic peroxidesuch as benzoyl peroxide as described in German Patent 823,- 449 toHenkel and Company.

The following examples illustrate the process of the invention and thevarious extensions thereof. In these examples, parts by weight (w.) andparts by volume (v.) bear the same relationship as the kilogram and thelitre. Temperatures are given in degrees centigrade.

2,2,6,6-tetrachlorocyclohexanone was prepared accord ing to thedirections given by R. Riemschneider (Monatsh., 1954, 85, 417).

EXAMPLE I Preparation of the cyanohydrin of 2,2,6,6-tetrachl0r0-cyclohexanane, i.e. 2,2,6,6-tetrachl0r0-1-hydroxyeycl0- hexanecarbonitrile To a stirred suspension of potassium cyanide W.) in ethanol(250 v.) at 0 was gradually added, first glacial acetic acid (22 v.),and then 2,2,6,6-tetrachlorocyclohexanone (20 w.) in ethanol (250 v.).The resulting mixture was kept overnight at room temperature, madestrongly acid by the addition of dilute sulfuric acid and diluted with alarge volume of water. The product was extracted with ether, and theextract washed with water, dried over magnesium sulfate and evaporated.The residual oil (22 w.) crystallized on standing in the refrigeratorand was recrystallized from a mixture of ether and light petroleum (B.P.40-60) at 0 to afford 2,2,6,6-tetrachlorol-hydroxycyclohexanecarbonitrile as needles (12 w.). The melting point of the cyanohydrinwas diffuse and variable, even after repeated recrystallization;analytically pure material was completely molten at temperatures rangingfrom about to The infra-red spectrum showed a band at 2.87 (0-H).

The mother-liquors from the first recrystallization were evaporated andthe residue was recrystallized from carbon tetrachloride to yield afurther quantity (5.4 w.) of the cyanohydrin (total yield 78%).

Analysis.-Found: C, 32.1; H, 2.8; Cl, 53.6; N, 5.2%. C H- ChNO requires:C, 32.0; H, 2.8; Cl, 53.9; N, 5.3%.

EXAMPLE II Preparation of2,6,6-trichl0ro-1,Z-epoocycyclohexanecarbonitrile (a) From2,2,6,6-tetrachlorocyclohexanone directly.- This preparation was carriedout by the method described in Example I using potassium cyanide (30 W.)in ethanol (300 v.), glacial acetic acid (15 v.), and 2,2,'6,6-tetrachlorocyclohexanone (25 w.) in ethanol (300 v.), the mixturebeing allowed to stand for one week. Working up as described in ExampleI yielded an oil (22 w.), which crystallized on standing in therefrigerator. Recrystallization from a mixture of ether and lightpetroleum (B.P. 40 to 60) at 0 furnished 2,6,6-trichloro-1,2-epoxycyclohexanecarbonitrile as prisms (13 w.) melting point 44-45",raised to 45-46 on further recrystallization. The infra-red spectrumshowed no O-H, C -O or 0 C bands, but exhibited a very weak band at4.41p. (C N).

A second crop of the epoxy-nitrile (6.3 w.), melting point 39.5 to 43.5was obtained from the mother-liquors of the above recrystallization(total yield 80%).

Analysis.Found: C, 37.0; H, 2.7; Cl 47.4; N, 6.5%. C I-I Cl NO'requires:C, 37.1; H, 2.7 Cl, 47.0; N, 6.2%.

(b) From the cyanohydrin of Example I by the action of potassiumcyanide-A mixture of the cyanohydrin (1.6 w.), potassium cyanide (1.6W.), and ethanol (15 v.) was kept at room-temperature for two days.Working up as described above then gave a quantitative yield of theepoxy-nitrile, melting point and mixed melting point 45 to 46 afterrecrystallization.

EXAMPLE III Preparation 0 1,2,2,6,6-pentachloracyclohexanecarbonitrile Amixture of the cyanohydrin of Example I (7.9 w.), thionyl chloride (25v.) and pyridine (0.3 v.) was refluxed for 6 hours. The excess thionylchloride was removed under reduced pressure and benzene was distilledfrom the residue (8.9 w.), which was then treated with methanol. Theresulting crystalline 1,2,2,6,6-pentachlorocyclohexanecarbonitrile (3.2W., 38%) was obtained on recrys' tallization from a mixture of ether andchloroform a: elongated prisms, melting point 182-183 C. The infra redspectrum showed a very weak band at about 4.43; (CEN).

Analysis.Found: C, 29.7; H, 2.2; N, 5.1%. C H Cl I requires: C, 29.9; H,2.1; N, 5.0%.

EXAMPLE IV Preparation of1-acet0xy-Z,2,6,6-tetrachl0rocyclohexanecarbonitrile (a) Using acetylchZ0ride.A mixture of cyanohydri of Example I (5.8 w.), acetyl chloride(25 v.), an pyridine (0.3 v.) was refluxed for 65 hours. The excesacetyl chloride was removed under reduced pressure an the crystallineresidue washed with methanol to affor1-acetoxy-2,2,6,6-tetrachlorocyclohexanecarbonitrile (2 w., 37% yield),melting at 1895-1905 after recrysta lization from chloroform. Theinfra-red spectrum show a band at 5.54; (CEO).

Analysis.Found: C, 35.3; H, 3.1; Cl, 46.3; N, 4.69 C H Cl NO requires:C, 35.4; H, 3.0; Cl. 46.5; N, 4.69

(b) Using acetic anhydride.A mixture of the cyan hydrin of Example I(4.3 w.), acetic anhydride (20 v and pyridine (0.3 v.) was heated for 5days in an oil bath maintained at 120 to 130 C.

The reaction mixture was cooled, poured into water and methanol wasadded. The resulting crystalline acetoxy nitrile (2.6 w.; 52% yield) wascollected, washed and recrystallized as above. It had melting point andmixed melting point 188 to 190.

(c) Using benzoyl chlride.A mixture of the cyanohydrin (5.0 w.), benzoylchloride v.) and pyridine (0.3 v.) was heated for 5 days in a bathmaintained at 120 to 130 C. Lower boiling material was then removed bydistillation at 0.15 mm. and the residue treated with methanol to afford1-benzoyloxy-2,2,6,6-tetrachlorocyclohexanecarbonitrile, M.P. 167.5 to168 C. after recrystallization from a mixture of chloroform andmethanol. Yield 7%.

Analysis-.Found: C, 46.3; H, 2.9; N, 3.8%. C H Cl NO requires: C, 45.8;H, 3.0; N, 3.8%.

EXAMPLE V Preparation of 2,6,6-trl'chl0ro 1,2-ep0xycyclohexanecarbonamide CONHz 0 Cl (a) From 2,6,6 trichloro 1,2epoxycyclohexanecarbonirrile.A mixture of the epoxy-nitrile (4.5 w.),potassium hydroxide (5.0 w.), ethanol (45 v.) and water (5 v.) was keptovernight at room temperature. The dark solution was poured into water,the crystalline product collected, washed with a little water and driedto give the desired amide, M.P. 145 to 146 C. (2.5 w.).Recrystallization from benzene afiorded needles M.P. 145.5 to 146.5 C.

Analysis-Foundc C, 34.7; H, 3.6; CI, 43.1; N, 5.6%. C H Cl NO requires:C, 34.4; H, 3.3; Cl, 43.5; N, 5.7%.

A further quantity of the epoxy-amide was obtained from the originalfiltrate by saturating it with sodium chloride. Total yield 82%.

(1')) From 2,2,6,6 tetrachloro 1 hydroxycyclolze arze carb0namide.Amixture of the hydroxy-amide (10 w.), potassium hydroxide (20* w.),ethanol (100 v.) and water (100 v.) was warmed on a boiling water bathfor minutes. Addition of brine then precipitated the epoxyarnide, M.P.and mixed M.P. 145 to 146 C. after recrystallization. Yield 76%.

EXAMPLE VI Preparation of2,2,6,6-tetrachl0ro-1-hydroxycyclohexanecarbonamid e (a) From thecyanohydrin of 2,2,6,6-tetrachlorocyclo 'zexanone.A solution of thecyanohydrin (5.1 W.) in :oncentrated sulfuric acid (10 v.) was warmed ona 'boilng water bath for 30 minutes and then poured into ice vater. Thecrystalline product was collected, washed with old water, dried andrecrystallized from benzene when t was obtained as needles of M.P. 202to 203. Yield 4%.

Analysis.Found: C, 30.0; H, 3.1; Cl, 50.0; N, 5.0%. H Cl NO requires: C,29.9; H, 3.2; Cl, 50.5; N, 5.0%.

(b) From 1,2,2,6,6 penzach[orocyclolzexanecarboni- -il'e.-The nitrile(8.2 w.) was dissolved in warm con- :ntrated sulfuric acid v.) withevolution of hydroen chloride. The resulting solution was then worked upabove to yield the hydroxyamide in 78% yield, M.P. 1d mixed M.P. 202 to203 after recrystallization from mixture of ether and light petroleum.

EXAMPLE VII Preparation of the compound of empirical formula C H cl NOand believed structure C ONH:

C1 HO 2,6,6 trichloro-l,Z-epoxycyclohexanecarbonamide (88 W.) wasdissolved in hot 50% sulfuric acid (70 v.) and the solution cooled anddiluted with water. The crystalline product was collected and washedwith water, affording the amide M.P. 195 to 196 C. with frothing afterrecrystallization from methanol. Yield 60%.

Analysis.Found: C, 34.4; H, 3.4; Cl, 43.2; N, 5.8%. C H Cl NO requires:C, 34.4; H, 3.3; C], 43.5; N, 5.7%.

The infra-red spectrum showed bands at 2.84, 2.94 and ca. 3.1, (OH andN-H) and at 5.94 (C O) and 5.38 1 (Amide II); there was an indication ofan unresolved band in the region characteristic of C=C.

To a solution of this amide (0.62 w.) in concentrated sulfuric acid (5v.) at 0 C. was added slowly an ice cold solution of sodium nitrite (0.7w.) in water (5 v.). The mixture was then heated on the steam bath for15 minutes and poured into water. The crude oily product (0.51 w.),collected by ether extraction, could not be induced to crystallize. Itdissolved in sodium bicarbonate solution with effervescence and itsinfra-red spectrum showed bands at ca. 2.9;. (O-H), 5.82 (C=O) and 6.22,(C=C). It was therefore concluded that the product was an unsaturatedcarboxylic acid. This result eliminated the 2,6,6trichloro-1-hydroxycyclohexanecarbonamide structure since this compoundwould he expected to afford a ketone under the reaction conditions. Thestructure given at the beginning of this example was therefore assignedto this product.

EXAMPLE VIII Preparation of 2,6-dicl1lorobenzonitrile (a) From 1,226.6pentachlorocycl'olzexanecarbonitrila-The chloro-nitrile (1.1 w.) washeated for one hour in an oil bath maintained at 225 to 235. Theresulting tar was extracted repeatedly with boiling light petroleum(B.P. 40 to 60), and the combined extracts were evaporated. The residuewas then kept at a temperature of 90 to under 20 mm. pressure in asublimation apparatus, afiording 2,6-dichlorobenzonitrile as a sublimate(0.45 w., 67% yield). Recrystallization from light petroleum (B.P. 4060)furnished needles, melting point and mixed melting point to 146.

(b) From I-acetoxy 2,2,6,6 teirachlorocyclohexanecarb0nitrile.Theacetoxy-nitrile (1.1 w.) was heated for 30 minutes in an oil bathmaintained at 260 to 270. The resulting tar was then worked up as aboveto yield 2,6-dichlorobenzonitrile (0.11 w, 18% yield).

(c) From 2,2,6,6 tetrachloro 1 hydrowycyclahexanecarb0namide.-A mixtureof the hydroxyarnide (25 w.) and phosphorus pentoxide (10 W.) was heatedfor 30 minutes in a bath maintained at 250 to 260 C. The cooled productwas collected in boiling ether, the ether removed and the residual2,6-dichlorobenzonitrile sublimed. Yield 19%.

(d) From the amide prepared according to Example VII.A mixture of theamide (10 w.) and phosphorus pentoxide 10 w.) was heated for one hour ina bath maintained at 220 to 230 and then worked up as described in (c)to give a 37% yield of 2,6-dichlorobenzonitrile M.P. 145.5 to l46.5after recrystallization from otherlight petroleum.

9 10 We claim as our invention: OTHER REFERENCES y Y Y Grewe et al.:Chemische Berichte, v01. 87, pages 794 and 79s (1954). References CltedMigrdichian: Organic Synthesis, vol. 1, page 429, New UNITED STATESPATENTS 5 YQYk, Remhold, 1957- 2,993,068 7/ 1961 Sohipper 260557 WALTERA. MODANCE, Primary Examiner.

3,027,248 3/1962 Koopman et a1 712.3 N. TROUSOF, Assistant Examiner.

